Lung cancer is an extraordinarily common, devastating and poorly understood disease responsible for ~160,000 deaths/year in the USA and 1.4 million deaths/year worldwide. Despite its prevalence and strikingly high mortality rates, the origins of the disease remain poorly understood and therapeutic approaches to treat lung cancer patients have proven disappointingly ineffective. The dismal prognosis for patients with advanced lung cancer emphasizes the urgent need for new chemotherapeutic approaches to treat this disease. The overarching, long-term goal of this research program is to aid development of rational therapeutic strategies to treat lung cancer patients, in full accord with the central mission of the National Cancer Institute. However, the immediate objective of this proposal is to explore the role of the Ras-activated RAF->MEK->ERK MAP kinase signal transduction pathway in the initiation, progression and therapy of lung cancer. This pathway is directly implicated in the aberrant physiology of lung cancer cells due to the prevalence of mutations in genes encoding the EGF receptor, KRAS or BRAF observed in primary patient specimens and human lung cancer derived cell lines. The central hypothesis of this grant proposal is that oncogenic KRasG12D or BRafV600E can initiate and maintain tumorigenesis in mouse models of human lung cancer through activation of the RAF->MEK->ERK pathway. Consequently we shall use genetically engineered KRasLSL and BRafCA mice, in which oncogene expression is initiated in the lung epithelium by infection with an adenovirus expressing Cre recombinase, to conduct an in-depth exploration of the role of oncogenic KRasG12D or BRafV600E in lung tumor initiation, progression and therapy. In Aim 1 we will conduct a head-to-head comparison between KRasG12D- and BRafV600E-induced lung tumorigenesis to determine why the former progresses to adenocarcinoma while the latter does not. Next, to test the importance of RAF->MEK->ERK signaling downstream of KRasG12D-induced lung tumorigenesis, we will test the anti-tumor effects of potent, specific and selective pharmacological inhibitors of either RAF (SB590885) or MEK1/2 (PD0325901) using the KRasLSL mouse model of lung tumorigenesis. In Aim 2 we will test the hypothesis that the loss of the Ink4a/Arf, Pten or Trp53 tumor suppressor genes can influence the response of KRasG12D- or BRafV600E-induced lung tumors to pharmacological inhibition of RAF or MEK using mice, and human and mouse lung cancer derived cell lines. Finally, in Aim 3, we will utilize our recently derived BRafFA mice, in which oncogenic BRafV600E expression is initiated by Flp recombinase, to assess how temporal dissociation of oncogene activation and tumor suppressor gene silencing influences tumor initiation, progression and senescence. Although this proposal is focused primarily on studies of the role of tumor suppressor and oncogene action on tumor biology and on mechanisms of drug response in mouse models of lung cancer, this research has potentially important translational significance in the design and evaluation of new targeted strategies to treat lung cancer patients.